Sexually dimorphic changes in the endocrine pancreas and skeletal muscle in young adulthood following intra-amniotic IGF-I treatment of growth-restricted fetal sheep

Fetal growth restriction (FGR) is associated with decreased insulin secretory capacity and decreased insulin sensitivity in muscle in adulthood. We investigated whether intra-amniotic IGF-I treatment in late gestation mitigated the adverse effects of FGR on the endocrine pancreas and skeletal muscle at 18 mo of age. Singleton-bearing ewes underwent uterine artery embolization between 103 and 107 days of gestational age, followed by 5 once-weekly intra-amniotic injections of 360-mu g IGF-I (FGRI) or saline (FGRS) and were compared with an unmanipulated control group (CON). We measured offspring pancreatic endocrine cell mass and pancreatic and skeletal muscle mRNA expression at 18 mo of age (n = 7-9/sex/group). Total alpha-cell mass was increased , similar to 225% in FGRI males versus CON and FGRS males, whereas beta-cell mass was not different between groups of either sex. Pancreatic mitochondria-related mRNA expression was increased in FGRS females versus CON (NRF1, MTATP6, UCP2), and FGRS males versus CON (TFAM, NRF1, UCP2) but was largely unchanged in FGRI males versus CON. In skeletal muscle, mitochondria-related mRNA expression was decreased in FGRS females versus CON (PPARGC1A, TFAM, NRF1, UCP2, MTATP6), FGRS males versus CON (NRF1 and UCP2), and FGRI females versus CON (TFAM and UCP2), with only MTATP6 expression decreased in FGRI males versus CON. Although the window during which IGF-I treatment was delivered was limited to the final 5 wk of gestation, IGF-I therapy of FGR altered the endocrine pancreas and skeletal muscle in a sex-specific manner in young adulthood. NEW & NOTEWORTHY Fetal growth restriction (FGR) is associated with compromised metabolic function throughout adulthood. Here, we explored the long-term effects of fetal IGF-I therapy on the adult pancreas and skeletal muscle. This is the first study demonstrating that IGF-I therapy of FGR has sex-specific long-term effects at both the tissue and molecular level on metabolically active tissues in adult sheep.